DESCRIPTION (Applicant's Abstract): This randomized, placebo-controlled, double-blind, multicenter clinical trial will assess the efficacy of adjunctive cyclic progesterone therapy in lessening the frequency of intractable seizures in women with localization related epilepsy. There is considerable scientific evidence to suggest that estrogen generally increases while progesterone decreases neuronal excitability and seizures. Preliminary open trials suggest that the cyclic administration of adjunctive natural progesterone supplement may lessen seizure frequency by over 50% in the majority of women with catamenially exacerbated intractable seizures. Oral synthetic progestins, in contrast, have not shown significant efficacy. Progesterone is not widely used as an adjunct to seizure management because its benefits have yet to be definitively demonstrated. The proposed clinical trial will require 640 subjects. During the baseline phase, seizure/menstrual charts will document baseline seizure frequency and determine if seizure occurrence shows a catamenial pattern of exacerbation. The subjects will be divided into catamenial and non-catamenial groups. Each group will be randomized in a 2:1 ratio into progesterone and placebo treatment groups. Seizure frequency during 3 months of treatment will be compared to baseline, while monitoring antiepileptic drug and hormone levels. The proposed clinical trial has considerable potential significance for women with epilepsy. Approximately 30% of women with epilepsy have refractory seizures, that is persistent seizures despite trials of antiepileptic drug, use. It is estimated that 35% of these women have catamenial seizure exacerbation. If, on the basis of preliminary observations, this group responds favorably to hormonal therapy, one would expect that progesterone may benefit approximately (1,000,000 x .30 x .35) 100,000 women with catamenial epilepsy and perhaps many more women with no a priori demonstrated hormonal sensitivity to seizure occurrence.